Dose thresholds should exist for chemical carcinogens.

To the Editor: Calculations showing that dose thresholds should exist for chemicalcarcinogens have been presented by this author in a series ofpublications (e.g., Waddell, 2002, 2003a–d). Subsequently,many investigators have challenged these calculations as flawed(e.g., Andersen et al., 2003; Crump and Clewell,     

Corticosteroidogenesis and StAR protein of rainbow trout disrupted by human-use pharmaceuticals: data for use in risk assessment.

Recent reports of presence of pharmaceutical drugs in surfacewaters (Kolpin et al., 2002; Metcalfe et al., 2004; Miao etal., 2002) raised concerns about the potential effects of thesechemicals in nontarget species, especially those in the aquaticenvironment (Trudeau et al., 2005). The study highlighted inthis issue, "Salicylate disrupts interrenal steroidogenesisand brain glucocorticoid receptor expression in rainbow trout"by Gravel and Vijayan (2006), demonstrated, using state-of-the-artmolecular tools in a well-characterized physiological modelrelevant for environmental toxicology, the disruption of corticosteroidogenesisby acetaminophen, ibuprofen, and salicylic acid, three human-usepharmaceuticals often detected in surface waters. Pharmaceuticals, substances designed to exert specific physiologicaleffects to prevent, cure, or alleviate symptoms of disease,include drugs,     

Focal adhesion kinase as a potential target in arsenic toxicity.

Arsenic is one of the highest priority hazardous substancesaround the world, and is well known for its toxicity and carcinogenicityin humans (National Research Council, 1999). Arsenic trioxidealso finds use as a remarkably effective chemotherapeutic agentin the treatment of acute promyelocytic leukaemia (APL), andmay find use in the treatment of certain solid tumors (Chenet al., 2002). This paradoxical nature of arsenic as a carcinogenicanti-cancer agent is dependent on the dose and duration of exposure,the status of various diseases, and the complex cellular interactionsof this remarkable metalloid (National Research Council, 1999;Qian et al., 2003). In this issue of Toxicological Sciences,Yancy et al. (pp. 1–9) reported the effects of sodium     

Reply

To the Editor: The issue of carcinogenicity of bisphenol A was discussed inprevious letters to the editor (Huff, 2001; Munro et al., 2002).In his letter revisiting the subject, we note that Huff (2002)does not present any new information that was not previouslyaddressed. As we have already commented on the NTP findingsin our earlier letter (Munro et al., 2002), we have chosen topresent additional information in support of our findings withregard to the lack of carcinogenic potential of bisphenol A.However, we would first like to indicate that our original response     

On the application of data on mode of action to carcinogenic risk assessment.

In the Forum article in this issue of Toxicological Sciences,Cohen et al. (2004) discuss a framework for systematic analysisof data on modes of carcinogenic action of chemicals in experimentalanimals, and its application to cancer risk assessment. Thissummarizes an exercise recently completed by the ILSI Risk ScienceInstitute (Cohen et al., 2003), which builds on a harmonizationinitiative of the International Programme on Chemical Safety(Sonich-Mullin et al., 2001). The framework approach is basedfundamentally on advances that have been achieved in recentdecades in understanding the pathogenesis of neoplasia. It isnow recognized that     

Guidelines governing conflict of interest.

In science, a conflict of interest may occur in situations wherefinancial or other personal considerations may bias the professionaljudgement of an investigator in conducting or reporting research.Conflicts may be real or perceived, harmful or insignificant.Whereas such conflicts may represent the potential for compromisedjudgement, they do not necessarily indicate the likelihood thatsuch bias will occur (Cohen, 2001; Flanagin, 2000; Friedman,1992).     

Paraquat: the red herring of Parkinson's disease research.

Definitions adapted from the American Heritage Dictionary

Redherring n 1: something that draws attention away from thecentralissue

n 2: a smoked herring having a reddish color (they turnredwhen cured)

Folklore suggests that criminals attemptingto throw off pursuingbloodhounds would rub the fish acrosstheir trail

Definition from Monty Python and the Holy Grail

Herring n 3:an implement for felling mighty trees as suggestedby misguidedknights

After the discovery that 1-methyl 4-phenyl 1,2,3,6-tetrahydropyridine(MPTP) induced a parkinsonian syndrome in individuals who inadvertentlyinjected the by-product of illicit drug manufacturing (Langstonet al., 1983; Ramachandiran et al., 2007; Richardson et al.,2005     

Highlight for phenols, quinolines, indoles, benzene and 2-cyclopenten-1-ones are oviduct toxicants in cigarette smoke, by Prue Talbot, Karen Riveles, and Ryan Rosa: list of tobacco-smoke constituents that are harmful for reproduction grows--passive smokers may be at risk.

Epidemiological studies provide compelling evidence that smokinghas serious negative consequences on fertility and pregnancyoutcome. Numerous epidemiological studies have linked smokingwith higher frequency of ectopic pregnancies and problems relatedto the oviduct function (Castles et al., 1999). Smoking decreasesthe success rate of in vitro fertilization and, more specifically,reduces the rates of oocyte production (reviewed by Shiverickand Salafia, 1999). Clearly, we do not understand the exactmechanisms by which smoking decreases fertility and negativelyaffects pregnancy outcome. One of the reasons is the complexcomposition of the cigarette smoke,     

Site-specific, dose-dependent transitional analysis of toxicologic mechanisms: the interplay of local metabolic and physicochemical saturation.

When animal exposures are used to assess human risk to inhaledchemicals, the animals generally receive higher dose rates overshorter periods of time. This difference in dose rate and durationof exposure, when applied to risk extrapolation, creates a keychallenge: the challenge of accounting for the impact of doseand dose rate on possible transitions in mechanisms of toxicity(Slikker et al., 2004a,b). One such transition and the relatedmicrodosimetry are the subject of this issue's highlighted articleIncreasing Exposure Levels Cause an Abrupt Change in the Absorption     

Nonanimal Alternatives for Skin Sensitization: A Step Forward?

For both animal welfare reasons as well as to meet the demandsof existing and impending legislation in Europe, there is anincreasing emphasis on the replacement of animals in toxicologytesting for end points such as skin sensitization (Basketterand Maxwell, 2007). However, many of the end points (chronictoxicity, teratology) may prove intractable, so there is a heavyfocus on end points such as irritation and sensitization. Inthis issue of Toxicological Sciences, there is a fascinatingnew paper by Natsch and Emter (2008) on how genes involved inthe response to antioxidants are impacted by exposure to chemicalswhich are     

Putting the fun into functional toxicogenomics.

The term "toxicogenomics" was first coined in 1999 to describethe marriage of toxicology and genomics (Nuwaysir et al., 1999).Since then, the field of toxicogenomics has undergone a rapidand uneven surge of growth. Driven by the promise of whole-genomegene expression analysis by microarray, toxicogenomics has beenadvanced as the tool for improved mechanistic toxicology screens,more sensitive and earlier toxicity discovery, drug and chemicalsafety assessments, and new drug discovery assays (Hayes andBradfield, 2005). However, it quickly became evident to scientistsconducting toxicogenomic studies that making sense of enormousdata sets from microarray studies would require new tools andnew approaches in order to     

Prenatal Exposure to Phthalates and Intrauterine Inflammation: A Unifying Hypothesis

We read with great interest the recent paper by Xu et al. (2005),showing that phthalates alter rat placental essential fattyacids (EFA) homeostasis via peroxisome proliferator-activated     

Communication Regarding Metabonomic Identification of Two Distinct Phenotypes in Sprague-Dawley (Crl:CD(SD)) Rats

In a recent publication, we reported the identification andcharacterization of two distinct phenotypes in Sprague-Dawleyrats obtained from the Charles River Raleigh facility (Roboskyet al., 2005). The phenotypes were designated as HIP (high hippuricacid level in urine) and CA (high chlorogenic     

Letter.

To the Editor: Kodavanti et al.(2003) induced cardiomyopathy in Wistar Kyotorats by inhalation exposure to environmental combustion particlessimilar to ambient particulate matter and rich in bioavailablezinc. Myocardial degeneration, inflammation, and     

Letter

To the Editor: In the article by Tirmenstein et al. (2002) the authors concludethat the initiating event in troglitazone (TRO) mediated toxicityto HepG2 cells is disruption of mitochondria. We agree withthe authors that the relevance of their findings to idiosyncratichepatotoxicity in TRO-treated     

In Vitro Cytotoxicity of Nanoparticles in Mammalian Germ-Line Stem Cell

Nanotechnology involves the creation and manipulation of materialsat nanoscale levels to create products that exhibit novel properties.There are important applications of nanoscience in biology andbiotechnology, and nanotechnology offers new tools to biologists(Whitesides, 2003). Nevertheless, despite the increased interest in the developmentof nanoparticles, few studies address their potential toxicity.The rapidly developing field of nanotechnology is likely tobecome yet another source of human exposure to nanoparticlesby different routes: inhalation, ingestion, dermal, and injection.Regulatory agencies, researchers, and health and environmentalwatchdogs are assessing how nanoscale materials affect humanhealth and the environment (Service, 2004). Similarly, the characteristic biokinetic behavior of nanoparticles     

TO THE EDITOR

Phalen et al. (2006) have opened an important discussion ona key question of in vitro dosing of cells with poorly solubleparticles, focusing on tracheobronchial epithelial cells. Indeed,this paper is very timely, given the increasing number of publicationsusing exorbitantly high in vitro doses of particles and extrapolatingfrom those results potential adverse     

Neurobehavioral effects of decabromodiphenyl ether (Deca) in neonatal mice.

To the Editor: May 13, 2004 Drs. Eriksson and Viberg responded to a Letter to the Editor(Vijverberg and van den Berg) regarding their report of neurobehavioraleffects of decabromodiphenyl ether (Deca) in neonatal mice (Toxicol.Sci. 76, 112–120; Viberg et al., 2003     

Troglitazone hepatotoxicity: are we getting closer to understanding idiosyncratic liver injury?

Idiosyncratic hepatotoxicity is a rare and unpredictable eventof liver injury affecting generally less than 1 in 10,000 patientstreated with certain drugs. However, it is a serious clinicalproblem as it accounts for 10% of all drug-induced liver failurecases (Kaplowitz, 2005). Since idiosyncratic drug reactionsare not detected in preclinical testing and in most cases noteven during clinical trials, the problem surfaces generallyafter the drug is approved and hundreds of thousands of patientsare being treated. Idiosyncratic hepatotoxicities are currentlythe main cause for Food and Drug Administration-mandated warnings,restrictions of use or even withdrawals of drugs from the market(Kaplowitz, 2005). As such, this is a considerable problem forthe pharmaceutical industry and for regulatory agencies worldwide.One of the recent examples of drugs causing idiosyncratic hepatotoxicityand liver failure was the antidiabetic drug Rezulin (troglitazone). Troglitazone, a peroxisome proliferator–activated     

TO THE EDITOR

Gaylor et al. (2004) described a method of estimating the "zero-equivalentdose" (ZED) and a lower confidence limit for it (LZED), basedupon a quadratic polynomial dose-response model. They also suggesteda way to use the Environmental Protection Agency (EPA) benchmarkdose software to estimate these values, which was to selectthe continuous-response polynomial model and to use the "Point"benchmark response (BMR) type, setting it equal to the